The invention relates to the compound (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-(6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-carbonitrile, pharmaceutical compositions of the compound, and methods of using the compound for the treatment of psychiatric disorders and neurological diseases including depression, anxiety related disorders, irritable bowel syndrome, addiction and negative aspects of drug and alcohol withdrawal, and other conditions associated with CRF.
Corticotropin releasing factor (CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland [Rivier, J. et al., Proc. Nat. Acad. Sci. (USA) 80: 4851 (1983); Vale, W. et al., Science 213: 1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [Vale, W. et al., Rec. Prog. Horm. Res. 39: 245 (1983); Koob, G. F. Persp. Behav. Med. 2: 39 (1985); De Souza, E. B. et al., J. Neurosci. 5: 3189 (1985)]. There is evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [Blalock, J. E. Physiological Reviews 69: 1 (1989); Morley, J. E. Life Sci. 41: 527 (1987)].
Over-expression or under-expression of CRF has been proposed as an underlying cause for several medical disorders. Such treatable disorders include affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorders, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia, hypertension, tachycardia and congestive heart failure, stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress [for reviews see McCarthy, J. R.; Heinrichs, S. C.; Grigoriadis, D. E. Cur. Pharm. Res. 5: 289-315 (1999); Gilligan, P. J.; Robertson, D. W.; Zaczek, R. J. Med. Chem. 43: 1641-1660 (2000), Chrousos, G. P. Int. J. Obesity, 24, Suppl. 2, S50-S55 (2000); Webster, E.; Torpy, D. J.; Elenkov, I. J.; Chrousos, G. P. Ann. N. Y. Acad. Sci. 840: 21-32 (1998); Newport, D. J.; Nemeroff, C. B. Curr. Opin. Neurobiology, 10: 211-218 (2000); Mastorakos, G.; Ilias, I. Ann, N.Y. Acad. Sci. 900: 95-106 (2000); Owens, M. J.; Nemeroff, C. B. Expert Opin. Invest. Drugs 8: 1849-1858 (1999); Koob, G. F. Ann. N.Y. Acad. Sci., 909: 170-185 (2000)].
There is evidence that CRF plays a role in affective disorders including depression (for example, major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression), dysthemia, bipolar disorders, and cyclothymia. In individuals afflicted with major depression, the concentration of CRF is significantly increased in the cerebrospinal fluid (CSF) of drug-free individuals [Nemeroff, C. B. et al., Science 226: 1342 (1984); Banki, C. M. et al., Am. J. Psychiatry 144: 873 (1987); France, R. D. et al., Biol. Psychiatry 28: 86 (1988); Arato, M. et al., Biol Psychiatry 25: 355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [Nemeroff, C. B. et al., Arch. Gen. Psychiatry 45: 577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [Gold, P. W. et al., Am J. Psychiatry 141: 619 (1984); Holsboer, F. et al., Psychoneuroendocrinology 9: 147 (1984); Gold, P. W. et al, New Eng. J. Med. 314: 1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [Sapolsky, R. M. Arch. Gen. Psychiatry 46: 1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2: 53 (1989)].
There is evidence that CRF plays a role in the etiology of anxiety and related disorders including anxiety with co-morbid depressive illness, panic disorder, phobic disorders, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and atypical anxiety disorders [The Merck Manual of Diagnosis and Therapy, 16th edition (1992)]. Emotional stress is often a precipitating factor in anxiety disorders, and such disorders generally respond to medications that lower response to stress. Excessive levels of CRF are known to produce anxiogenic effects in animal models [see Britton, D. R. et al., Life Sci. 31: 363 (1982); Berridge, C. W., Dunn, A. J. Regul. Peptides 16: 83 (1986); Berridge, C. W.; Dunn, A. J. Horm. Behav. 21: 393 (1987)]. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [Britton, D. R. et al., Life Sci. 31: 363 (1982); Berridge, C. W., Dunn, A. J. Regul. Peptides 16: 83 (1986)]. Preliminary studies using the putative CRF receptor antagonist α-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces “anxiolytic-like” effects that are qualitatively similar to the benzodiazepines [Berridge, C. W.; Dunn, A. J. Horm. Behav. 21: 393 (1987), Dunn, A. J.; Berridge, C. W. Brain Research Reviews 15: 71 (1990)].
Neurochemical, endocrine, and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics, providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the “anxiogenic” effects of CRF in both the conflict test [Britton, K. T. et al. Psychopharmacology 86: 170 (1985); Britton, K. T. et al. Psychopharmacology 94: 306 (1988)] and in the acoustic startle test [Swerdlow, N. R. et al. Psychopharmacology 88: 147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [Britton, K. T. et al. Psychopharmacology 94: 306 (1988)]. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (α-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces “anxiolytic-like” effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p 221 (1990)].
In addition to modulating the HPA-axis, CRF is considered to be a key modulator of the gut-brain axis. Evidence exists indicating that CRF may play a role in mediating stress-related gastrointestinal disorders [Gabry, K. E. et al. Molecular Psychiatry 7(5): 474-483 (2002)] such as irritable bowel syndrome (IBS), post-operative ileus, and colonic hypersensitivity associated with psychopathological disturbance and stress [for reviews see E. D. DeSouza, C. B. Nemeroff, Editors; Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p 221 (1990) and Maillot C. et al. Gastroenterology, 119: 1569-1579 (2000); Fukudo, S. J. Gastroenterol, 42 (Suppl XVII): 48 (2007); Taché, Y.; Bonaz, B. J. Clin. Invest. 117: 33 (2007)]. In rats it has been demonstrated that i.p. administration of CRF1 antagonist JTC-017 blocked an increase in fecal output induced by exposure to chronic colorectal distention [Saito, K. et al. Gastroenterol., 129: 1533 (2005)]. Additionally, JTC-017 attenuated the anxiety-related behavior seen after exposure to acute colorectal distention. CRF-stimulated colonic motility in rats was also attenuated by central administration of CRF1/2 peptide antagonist astressin [Tsukamoto, K. et al. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290: RI 537 (2006)]. In healthy humans, i.v. administration of CRF was shown to affect rectal hypersensitivity and mimic a stress-induced visceral response specific to IBS patients [Nozu, T.; Kudaira, M. J. Gastroenterol. 41: 740 (2006)]. These data suggest that CRF antagonists may be useful for the treatment of IBS.
Antagonists of CRF1 have been examined for use as treatments for addiction and the negative aspects of drug withdrawal [Steckler, T.; Dautzenberg, F. M. CNS Neurol. Disord. Drug Targets 5: 147 (2006)]. Withdrawal from nicotine, cocaine, opiates, and alcohol often leads to a negative emotional state and elevated levels of anxiety. These undesirable effects can sometimes be counteracted by increasing self administration of the substance, which leads to relapse to the addicted state. External stressors can often lead to a relapse in abuse as well.
CRF receptor antagonists may be useful for treatment of the negative affective aspects of withdrawal from nicotine. Pretreatment of nicotine dependent rats with CRF1/2 peptide antagonist D-Phe CRF(12-41) was shown to prevent the elevations in brain reward threshold associated with nicotine withdrawal [Bruijnzeel, A. W. et al. Neuropsychopharmacol. 32: 955 (2007)]. D-Phe CRF(12-41) also caused a decrease in stress-induced reinstatement of nicotine-seeking behavior in rats [Zislis, G. et al. Neuropharmacol. 53: 958 (2007)]. Additionally, an increase in nicotine intake after a period of abstinence, often seen with nicotine dependence, could be blocked in rats by pretreatment with the CRF1 antagonist MPZP [Specio, S. E. et al. Psychopharmacol. 196: 473 (2008); George, O. et al. Proc. Natl. Acad. Sci. U.S.A. 104: 17198 (2007)].
Evidence from animal studies also suggests that the effects of cocaine and morphine withdrawal and relapse may be attenuated by antagonism of the CRF receptor. The CRF1 antagonist CP-154,526 was shown to attenuate spiradoline-induced reinstatement of cocaine seeking behavior in squirrel monkeys [Valdez, G. R. et al. J. Pharm. Exp. Ther. 323: 525 (2007)] as well as cue-induced reinstatement of methamphetamine-seeking behavior in rats [Moffett, M. C. et al. Psychopharmacol. 190: 171 (2007)]. Lorazepam dependent rats pretreated with CRF1 antagonist R121919 [Holsboer, F. et al. Eur. J. Pharmacol. 583: 350 (2008)] before precipitation of withdrawal showed reduced HPA axis activation and reduced anxiety behaviors in the defensive withdrawal model [Skelton, K. H. et al. Psychopharmacol. 192: 385 (2007)]. R121919 was similarly able to attenuate the severity of precipitated morphine withdrawal and withdrawal-induced HPA axis activation [Skelton, K. H. et al. Eur. J. Pharmacol. 571: 17 (2007)]. The amount of opiate exposure during self-administration as well as the length of abstinence can affect relapse. Rats allowed to self-administer cocaine for longer periods of time (6 h daily) were more susceptible to reinstatement by cocaine, electric foot shock, or administered CRF than those allowed to self-administer for shorter periods (2 h daily) [Mantsch, J. R. et al. Psychopharmacol. 195: 591 (2008)]. In another study, CRF1 antagonists MPZP and antalarmin were shown to reduce cocaine self-administration in rats with extended daily cocaine access [Specio, S. E. Psychopharmacol. 196: 473 (2008)].
There is evidence suggesting that CRF1 antagonists may help block the negative emotional aspects, excessive alcohol drinking, and stress-induced relapse seen in ethanol dependence [Heilig, M. et al. Trends Neurosci. 30: 399 (2007)]. Ethanol-dependent wild-type mice show an increase in ethanol self-administration during withdrawal, but only after a period of abstinence [Chu, K. G. F. Pharmacol. Biochem. Behav. 86: 813 (2007)]. This effect was reversed by administration of the CRF1 antagonist antalarmin. CRF1 knockout (KO) mice do not show this tendency toward increased self-administration. When treated with CRF1 antagonists R121919 or antalarmin, ethanol-dependent rats showed a reduction in excessive ethanol self-administration during acute withdrawal [Funk, C. K. et al. Biol. Psychiatry 61: 78 (2007)]. Non-dependent rats treated with these CRF1 antagonists, however, showed no effect on ethanol self-administration. Similarly, CRF1 antagonist MPZP selectively reduced excessive ethanol self-administration during acute withdrawal in dependent rats [Richardson, H. N. et al. Pharmacol. Biochem. Behav. 88: 497 (2008)]. In another study, a novel CRF1 antagonist selectively reduced excessive ethanol self-administration induced by stress in dependent rats [Gehlert, D. R. et al. J. Neurosci. 27: 2718 (2007)]. These studies demonstrate that antagonism of CRF1 receptors can selectively block excessive ethanol self-administration without affecting basal self-administration levels. This suggests that CRF1 antagonists could be useful for the treatment of alcohol dependence.
It has been further postulated that CRF has a role in cardiovascular or heart-related diseases arising from stress such as hypertension, tachycardia and congestive heart failure, stroke (methods for using CRF1 antagonists to treat congestive heart failure are described in U.S. patent application Ser. No. 09/248,073, filed Feb. 10, 1999, now U.S. Pat. No. 6,043,260 (Mar. 28, 2000).
It has also been suggested that CRF1 antagonists are useful for treating arthritis and inflammation disorders [Webster, E. L. et al. J. Rheumatol. 29(6): 1252-61 (2002); Murphy, E. P. et al. Arthritis Rheum. 44(4): 782-93 (2001)].
It has also been suggested that CRF1 antagonists are useful for skin disorders [Zouboulis, C. C. et al. Proc. Natl. Acad. Sci. 99: 7148-7153 (2002)]. Stress-induced exacerbation of chronic contact dermatitis was blocked by a selective CRF1 antagonist in an animal model, suggesting that CRF1 is involved in the stress-induced exacerbation of chronic contact dermatitis and that CRF1 antagonist may be useful for treating this disorder [Kaneko, K. et al. Exp. Dermatol, 12(1): 47-52 (2003)].
Studies have demonstrated that CRF1 antagonists may be useful as hair growth stimulators (WO2002/19975 discloses cell culture assays for the use of CRF antagonists in stimulating KBM-2 cell production). Thus, CRF antagonists may be useful in treatment of hair loss.